Phase I/Randomized Phase II Study of Second Line Therapy With Irinotecan + Cetuximab +/- RAD001 for Colorectal Cancer

OUTLINE: This is a multi-center study.

PHASE I:

• UGT1A1 *28 7/7 genotype IS NOT present
• Cetuximab 250 mg/m2 IV days 1, 8, and 15
• Irinotecan 125 mg/m2 IV days 1 and 8
• RAD001 PO QD (dose determined at the time of registration; subjects will remain at this dose level until treatment discontinuation)

PHASE II:

• Randomization based on UGT1A1 *28 7/7 Genotype or Prior Irinotecan Exposure

ARM A:

• Cetuximab 250 mg/m2 IV days 1, 8, and 15
• Irinotecan 125 mg/m2 IV days 1 and 8

AT TIME OF PROGRESSIVE DISEASE, ARM A TREATMENT WILL CROSSOVER:

• Cetuximab 250 mg/m2 IV days 1, 8, and 15
• Irinotecan 125 mg/m2 IV days 1 and 8
• RAD001 PO QD (maximum tolerated dose)

ARM B:

• Cetuximab 250 mg/m2 IV days 1, 8, and 15
• Irinotecan 125 mg/m2 IV days 1 and 8
• RAD001 PO QD (maximum tolerated dose)

AT TIME OF PROGRESSIVE DISEASE, ARM B TREATMENT WILL BE DISCONTINUED

ECOG performance status 0-2

Life Expectancy: Not specified

Hematopoietic:

• Absolute neutrophil count (ANC) ? 1,500 mm3
• Platelets ? 100,000 mm3
• Hemoglobin (Hgb) ? 9 g/dL
• White blood cell count (WBC) ? 2,000 mm3
• INR < 1.5 x upper limit of normal (ULN) if not on anticoagulation (if on anticoagulation must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin)
• PTT < 1.5 x ULN

Hepatic:

• Bilirubin ? 1.5 x ULN
• Aspartate aminotransferase (AST, SGOT) ? 2.5 x ULN
• Alanine aminotransferase (ALT, SGPT) ? 2.5 x ULN
• Albumin ? 3.0 g/dL

Renal:

• Calculated creatinine clearance of ? 60 cc/min using the Cockcroft-Gault formula

Cardiovascular:

• No uncontrolled cardiac arrhythmia requiring medication, transient ischemic attack (TIA), or cerebrovascular accident (CVA) within 6 months prior to being registered for protocol therapy
• No uncontrolled congestive heart failure, myocardial infarction, or unstable angina within 6 months prior to being registered for protocol therapy

Pulmonary:

• No severely impaired lung function as demonstrated by pulse O2 saturation ? 90% at rest on room air, or pulmonary function test FEV1 ? 2L
• No history of prior chronic lung infection such as tuberculosis, atypical tuberculosis, or histoplasmosis as evidenced by a chest CT or x-ray within 21 days prior to being registered for protocol therapy

• Drug: Irinotecan
  Irinotecan 125 mg/m2 IV days 1 and 8
• Biological: Cetuximab
  Cetuximab 250mg/m2 IV days 1, 8 and 15
• Biological: RAD001
  Patients on Arm A will crossover and receive RAD001 at disease progression

• Active Comparator: Arm A: Irinotecan + Cetuximab +/- RAD001
  Interventions:

  • Drug: Irinotecan
  • Biological: Cetuximab
  • Biological: RAD001
• Active Comparator: Arm B: Ironotecan + Cetuximab
  Interventions:

  • Drug: Irinotecan
  • Biological: Cetuximab

Inclusion Criteria:

• Histological or cytological proof of colon or rectal adenocarcinoma
• Measurable site of disease according to RECIST that has not been previously irradiated
• Must have metastatic colorectal cancer which progressed after first line chemotherapy +/- bevacizumab
• Blood sample collected within 21 days prior to being registered for protocol therapy for UTG1A1 genotype analysis. (Patients with the UGT1A1 *28 7/7 genotype (homozygosity for the TA7 allele) will be excluded from the Phase I stage of the study. During the Phase II stage of the study, subjects will be allowed to participate but must begin treatment at dose level -1 of irinotecan.)
• A history of other malignancies (non-colorectal) is allowed, provided it has been curatively treated and demonstrates no evidence for recurrence of that cancer
• Prior radiation therapy allowed to < 25% of the bone marrow
• Age ? 18 years at the time of consent
• Written informed consent and HIPAA authorization for release of personal health information
• Females of childbearing potential and males must be willing to use an effective method of contraception
• Females of childbearing potential must have a negative pregnancy test within 7 days of being registered for protocol therapy

Exclusion Criteria:

• No more than one prior chemotherapy regimen for metastatic colorectal cancer, at least 28 days prior to being registered for protocol therapy
• No prior treatment with cetuximab
• No prior treatment with an mTOR inhibitor
• No known hypersensitivity to cetuximab, RAD001 (everolimus), other rapamycins (sirolimus, temsirolimus) or to its excipients
• No treatment with any investigational agent within 28 days prior to being registered for protocol therapy
• No symptomatic brain metastasis
• No uncontrolled diabetes as defined by a fasting serum glucose >1.5 x ULN
• No chronic treatment with systemic steroids or another immuno-suppressive agent
• No serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to being registered for protocol therapy
• No liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
• No active bleeding or a pathological condition that is associated with a high risk of bleeding
• No uncontrolled systemic disease including active infections or uncontrolled hypertension
• No known history of HIV seropositivity
• No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• No nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with protocol therapy
• No planned immunization with attenuated live viruses during the study period
• Females must not be breastfeeding

• Novartis Pharmaceuticals
• Pfizer